According to Classification of Chronic Pain published by International Association for the Study of Pain (IASP) in 1994, “pain” is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms such damage”.
Pain is mainly classified into (1) “nociceptive pain” seemingly caused by continuous stimulation of nociceptors; (2) “neurogenic pain” caused by a dysfunction in nerve fibers participating in the mechanism of transmitting and/or suppressing pain; and (3) “psychogenic pain” focusing on emotional and/or affective points.
Among these pains, neurogenic pain is an intractable pain which arises as the results of a dysfunction in the peripheral or central nerve system. It is considered that neurogenic pain is caused by, for example, compression, a trauma or an injury of peripheral nerve, a nerve plexus or a perineural soft tissue, or a damage in a central somatosensory pathway (for example, an ascending somatosensory pathway at the level of spinal cord, brain stem, thalamus or cortex) and so forth. More specifically, it might be induced by a neurodegenerative disease, an oseteodegenerative disease, a metabolic error (for example, diabetes), cancer, infection, inflammation, ischemia, a surgical operation, trauma, radiotherapy, the administration of an anticancer agent and so forth.
Although the mechanism of neurogenic pain onset still remains unknown in many points, it is assumed that the mechanism comprises spontaneous firing in sensory nerve caused by a newly expressed ion channel of a certain type, protrusion of sensory nerve fibers into various layers of the spinal cord, and changes in the expression of various neurotransmitters and receptors in the sensory nerve and spinal cord. Typical symptoms of neurogenic pain include allodynia, hyperalgesia, hyperesthesia and the like. These symptoms present characteristic pains just like as “burned”, “pin-pricked”, “getting an electrical shock”, etc. It has been known that neurogenic pain can be hardly overcome not only by using analgesics which are effective on common nociceptive pain but also even by using narcotic analgesics (The Lancet, 353, 1959-1966, 1999). For example, it is known that morphine, which has a potent analgesic effect on nocuous pain, shows only an insufficient effect on neurogenic pain. Since the insufficient analgesic effect of morphine is large feature of neurogenic pain, it is used in diagnosing neurogenic pain (Igaku no Ayumi, 189(10), 751-755, 1999). It is considered that the reason for the non-effectiveness of morphine on neurogenic pain is the denaturation of inhibitory neurons or a decrease in opioid receptors due to functional or morphological changes caused by neuropathy (Saishin Nou to Shinkeikagaku Sirizu, vol. 6, Itami no Shinkeikagaku, published by Medical View, 97, 1997).
As described above, allodynia is one of the typical symptoms of neurogenic pain. Allodynia means a state of suffering from a pain due to a stimulus which does not provoke any pain in normal people. In allodynia, even a non-noxious stimulus such as a light touch or compression, or moderate cold or warmth induces a pain. Namely, the fundamental characteristics of allodynia are that having a qualitative conversion of sensory response and the threshold thereof per se is lowered. In postherpetic neuralgia that is a typical example of neurogenic pain, allodynia is observed in 87% of patients and it is reported that the pain level in postherpetic neuralgia is proportional to the severity of allodynia. Since allodynia is a symptom which seriously decreases the QOL of patients with neurogenic pain including postherpetic neuralgia, it has attracted public attention as a highly important subject to be treated.
As a method for treating neurogenic pain, neurosurgical therapies such as nerve block and spinal epidural electrical stimulus (Igaku no Ayumi, 189(10), 757-762, 1999), gabapentinoids such as gabapentin and pregabalin, N-type calcium channel inhibitors such as ziconotide, tricyclic antidepressants (Rinsho to Yakubutsu Chiryo, 18(7), 643-646, 1999), antiepileptics, local anesthetics, baclofen and so forth are used. However, no safe and efficacious therapeutic method has been established yet. Therefore, it has been urgently required to develop a therapeutic agent which is effective for neurogenic pain.
On the other hand, it is reported that (2R)-2-propyloctanoic acid is a compound which can improve the function of abnormally activated astrocytes and can be used as an agent for prevention or treatment of various cranial nerve diseases including cerebral stroke since it has an effect of reducing intracellular S100β content (see, for example, Journal of cerebral blood flow & metabolism, 22(6), 723-734, 2002: Non-Patent Document 1).
It is also known that pentanoic acid derivatives including (2R)-2-propyloctanoic acid have an effect of improving the function of astrocytes and are useful as an agent for improving brain function. For example, they can be used in treatment of Alzheimer's disease, amyotrophic lateral sclerosis, neurological dysfunction of cerebral stroke or brain injury and so forth. Concerning dosing, it is reported that such a compound is orally administered to an adult in an amount per dose of from 1 to 1000 mg once to several times per day, or parenterally administered in an amount per dose of from 0.1 to 100 mg once to several times per day (see, for example, the specification of European Patent 0632008; Patent Document 1).
However, it has never been reported so far that (2R)-2-propyloctanoic acid is useful against a pain, in particular, a neurogenic pain.
[Non-Patent Document 1] Journal of cerebral blood flow & metabolism, 22(6), 723-734, 2002
[Patent Document 1] specification of European Patent